Dihydroethanoanthracene derivatives

ABSTRACT

Dihydroethanoanthracene derivatives of the formula: ##STR1## [wherein R represents a hydrogen or C 1  -C 4  alkyl; R 1  represents a group ##STR2## (in which A represents a C 2  -C 4  alkylene optionally substituted by one or two C 1  -C 4  alkyls or by a phenyl; and Y represents an oxygen, sulfur, or imino) or group 
     
         --COO--A--NH.sub.2 
    
     (in which A is as defined above)] and their pharmaceutically acceptable acid addition salts, being useful as antidepressants or their synthetic intermediates.

The present application is a divisional of application Ser. No. 692,941,filed June 4, 1976, now U.S. Pat. No. 4,061,854.

The present invention relates to dihydroethanoanthracene derivatives andtheir pharmaceutically acceptable acid addition salts being useful asantidepressants or their synthetic intermediates. More particularly,this invention relates to dihydroethanoanthracene derivatives of theformula: ##STR3## [wherein R represents a hydrogen or C₁ -C₄ alkyl; andR¹ represents a group ##STR4## (in which A represents a C₂ -C₄ alkyleneoptionally substituted by one or two C₁ -C₄ alkyls or by a phenyl; and Yrepresents an oxygen, sulfur, or imino) or group

    --COO--A--NH.sub.2

(in which A is as defined above)] and their pharmaceutically acceptableacid addition salts.

In said definition, the alkyl involves methyl, ethyl, propyl, isopropyl,butyl, and isobutyl, and the alkylene involves ethylene, trimethylene,and tetramethylene.

The dihydroethanoanthracene derivatives (I) can be prepared by reactinga nitrile of the formula: ##STR5## [wherein R is as defined above] withan amine of the formula:

    H.sub.2 N--A--Y--H                                         (III)

[wherein A and Y each is as defined above] to give a cyclic imine of theformula: ##STR6## [wherein A, R, and Y each is as defined above]; orhydrolyzing the cyclic imine, when Y is oxygen, to give an ester of theformula: ##STR7## [wherein A and R each is as defined above].

The preparation of the dihydroethanoanthracene derivatives (I) is shownin the following scheme: ##STR8## [wherein A, R, and Y each is asdefined above].

Accordingly, the dihydroethanoanthracene derivatives (I) can be preparedin two steps. At first, the reaction of the nitrile (II) with the amine(III) is carried out under heating, if necessary, in the presence of asuitable accelerator (e.g. zinc chloride, zinc acetate, aluminumchloride, hydrogen sulfide). A suitable inert solvent (e.g. benzene,toluene, xylene, dioxane, halobenzene) may be added, if necessary. Thusobtained cyclic imine (Ia) is occasionally converted into suitableorganic or inorganic acid addition salts (e.g. hydrochloride, nitrate,acetate, succinate, methanesulfonate). The cyclic imine (Ia) is preparedin a mixture of stereoisomers, depending on the sort of the startingnitrile (II) and amine (III), and the isomers may be purified in a formof mixture or be resoluted into individual isomers in a conventionalmanner.

Secondly, the hydrolysis of the cyclic imine (Ia), when Y is oxygen, iscarried out by treating with at least one mol equivalent of an aqueousacid (e.g. hydrochloric acid, sulfuric acid, nitric acid) at roomtemperature or under cooling or heating. If necessary, a suitablesolvent (e.g. water, alcohols, dioxane) may be used. Thus-obtained ester(Ib) can be collected either in a form of a salt of the acid above usedor in a form of free amine by treating said salt with a suitable base(e.g. sodium bicarbonate, ammonia, pyridine). So, the salt can beconverted into a salt of another acid such as organic acid (e.g.succinic acid, acetic acid, methanesulfonic acid).

The starting nitrile (II) can be prepared by reacting anthracene with anacrylonitrile (IV), as shown in the following scheme: ##STR9## [whereinR is as defined above].

The objective dihydroethanoanthracene derivatives (I) involves thecyclic imine (Ia) and ester (Ib). These dihydroethanoanthracenederivatives (I) and their pharmaceutically acceptable acid additionsalts are useful as antidepressants or their synthetic intermediates,showing an excellent central nervous activity, in particular antiptoticactivity against reserpine. For example, 2-aminoethyl9,10-dihydro-9,10-ethanoanthracene-11-carboxylate hydrochloride showedED₅₀ 30 mg/kg (mouse, per os) with LD₅₀ 902 mg/kg; and11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene showed ED₅₀ 41mg/kg (mouse, per os) in the antiptotic activity against reserpine withLD₅₀ 3536 mg/kg. The other objective compounds (I) showed similarpharmacological activities.

The dihydroethanoanthracene derivatives (I) and their pharmaceuticallyacceptable acid addition salts are applied singly or in combination withpharmaceutically suitable carriers such as wheat starch, corn starch,potato starch, gelatin, water etc. The choice of carriers is determinedby the preferred route of administration, the solubility of thesubstance, and standard pharmaceutical practice. Examples ofpharmaceutical preparations are tablets, capsules, pills, suspensions,syrups, powders, and solutions. These compositions can be prepared in aconventional manner. A suitable dosage of the dihydroethanoanthracenederivatives (I) or their pharmaceutically acceptable acid addition saltsfor adults is in the order of about 15 to 750 mg/day.

Presently-preferred and practical embodiments of the present inventionare illustratively shown in the following examples.

EXAMPLE 1

(1) A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g),ethanolamine (1.8 g) and zinc acetate (250 mg) is stirred at 130° C. for5 hours. The reaction mixture is dissolved in benzene and passed througha column of 10% hydrated alumina. The eluate is evaporated to remove thesolvent, and the residue is recrystallized from ether to give11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (3.3 g) ascrystals melting at 155 to 156° C. IR (KBr), 1655 cm⁻¹ (O--C═N).

(2) A solution of11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.122 g) in1.074 N hydrochloric acid (13.9 ml) is allowed to stand at roomtemperature for 2.5 hours. The reaction mixture is mixed with dioxane todissolve the precipitate formed and evaporated at room temperature underreduced pressure to remove the solvent. The residue is recrystallizedfrom anhydrous ethanol-ether to give 2-aminoethyl9,10-dihydro-9,10-ethanoanthracene-11-carboxylate hydrochloride 1/2hydrate (4.641 g) as crystals melting at 155 to 158° C. IR (Nujol),3379, 1735 cm⁻¹.

EXAMPLE 2

A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g),ethylenediamine (1.5 g) and hydrogen sulfide (about 100 mg) is stirredat 130° C. for 20 hours. The reaction mixture is mixed with water andether to be distributed in two layers. The ether layer is washed withwater, dried, and evaporated to remove the ether. The residue isrecrystallized from ether to give11-(2-imidazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (5.0 g) ascrude crystals. IR (KBr), 1621 cm⁻¹ (N--C═N).

EXAMPLE 3

A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g) and2-aminoethanethiol (2.0 g) is stirred at 130° C. for 4 hours. Thereaction mixture is recrystallized from ethanol to give11-(2-thiazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.5 g) ascrystals melting at 160 to 161° C. IR (KBr), 1619 cm⁻¹ (S--C═N).

EXAMPLES 4-9

Using the starting materials (II) and (III), the reactions each iscarried out as in Example 1 (1), whereby the corresponding products (Ia)are obtained.

    ______________________________________                                         ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                    Ex.   II      III         Ia                                                  ______________________________________                                        No.   R       A           m.p. (° C)                                                                      IR (cm.sup.-1)                             ______________________________________                                        4     H                                                                                      ##STR13##  190-191  1656 (CHCl.sub.3)                          5     H                                                                                      ##STR14##  118-120.sup.a                                                                          1658 (CHCl.sub.3)                          6     H                                                                                      ##STR15##  187-189.sup.b                                                                          1655 (CHCl.sub.3)                                H         "         116.5-118.sup.c                                                                        1659 (CHCl.sub.3)                          7     H                                                                                      ##STR16##  150-151.sup.d                                                                          1664 (Nujol)                                     H         "         115-117.sup.e                                                                          1652 (Nujol)                               8     Me      (CH.sub.2).sub.2                                                                          129-134  1654 (CHCl.sub.3)                          9     H       (CH.sub.2).sub.3                                                                          165-169  1673, 1660.5                                                                  (CHCl.sub.3)                               ______________________________________                                         Note:                                                                         The abbreviations in the table each has the following significance:           H (Hydrogen);                                                                 Me (Methyl group);                                                            Ph (Phenyl group);                                                            m.p. (Melting point);                                                         IR (Infra red absorption spectre);                                            .sup.a a mixture of diastereoisomers;                                         two combinations .sup.b,c and .sup.d,e ,                                      other diastereoisomers respectively.                                     

EXAMPLES 10-11

    ______________________________________                                         ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                    Ex.  Ia               Ib                                                      No.  R       OAN          m.p. (° C)                                                                       IR (cm.sup.-1)                            ______________________________________                                        10   H                                                                                      ##STR20##   169-171 (HCl)                                                                           1726 (Nujol)                              11   CH.sub.3                                                                              CH.sub.2CH.sub.2                                                                           190-193 (HCl)                                                                           1737 (CHCl.sub.3)                         ______________________________________                                         Note:                                                                         The abbreviations each is as defined above.                              

What is claimed is:
 1. A member selected from the group consisting of acompound of the formula ##STR21## wherein R represents hydrogen or C₁-C₄ alkyl, and A represents a member selected from the group consistingof C₂ -C₄ alkylene and C₂ -C₄ alkylene substituted by one or two C₁ -C₄alkyl moieties or by phenyl, and a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound according to claim 1 wherein R ishydrogen and A is C₂ -C₃ alkylene.
 3. A compound according to claim 1,namely 2-aminoethyl 9,10-dihydro-9,10-ethanoanthracene-11-carboxylate.4. A compound according to claim 1, namely 2-aminoethyl11-methyl-9,10-dihydro-9,10-ethanoanthracene-11-carboxylate.
 5. Acompound according to claim 1, namely 1-methyl-2-aminoethyl9,10-dihydro-9,10-ethanoanthracene-11-carboxylate.